RUI: Understanding Steroid Regulation of Ionotropic Glutamate Receptors

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Intellectual MeritThere are many mechanisms by which communication between neurons is regulated. Glutamate, the major fast excitatory neurotransmitter in the central nervous system, has, as one of its prime targets, the ionotropic glutamate receptors (iGluRs) which reside in the postsynaptic neural membrane. Ionotropic glutamate receptors are a family of ligand gated ion channels, which include AMPA, kainate, and NMDA receptors. Upon binding to glutamate, the opening of a nonselective cation channel allows an influx of positive charge, leading to postsynaptic cell depolarization, and hence propagation of the action potential. These receptors are carefully regulated. The endogenous sulfated steroids, pregnenolone sulfate and pregnenolone sulfate, which are structurally very similar, have been shown to differentially regulate these receptors. Previous research from the Gentile lab has shown that these steroids bind to one of two extracellular domains, dependant upon the iGluR family member. Using this as a platform, a combination of high resolution structural studies, computational studies, and mutational analysis will now allow for an understanding of this regulation on a detailed molecular level. The goal is to understand which binding events and conformational changes lead to an opening of the iGluR channel (and propagation of the action potential) and which lead to its closing.Broader Impacts The broader impacts of this project are focused both on exciting and training the next generation of students in the process of scientific discovery. This research will provide high quality, outcome-oriented, interdisciplinary training to undergraduates at the University of Richmond (UR). In addition, it will involve high school chemistry and biology teachers in Richmond, VA in an inquiry based investigation, which will enable them to develop new techniques ranging in scope from biophysics to molecular biology, gather ideas to incorporate into new courses or labs, earn professional development points, and introduce them to UR faculty that can serve as future mentors. It will also involve high school students in summer research, which will allow them to develop critical thinking and problem solving skills, as well as to expose them to the excitement of science.